tbuckley/cabot-search huggingface dataset:
Design, reporting, and disparities of advanced non–small cell lung cancer phase 3 clinical trials in the era of immunotherapy.
Authors: Isabele Ayumi Miyawaki, Lucas Pari Mitre, Fabio Ynoe de Moraes
Journal: Journal of Clinical Oncology (2023)

e13616 Background: Lung cancer remains the main cause of cancer-related mortality globally, with non-small cell (NSCLC) accounting for the majority of cases. The advent of immunotherapy (IO) has expanded treatment options for advanced NSCLC. However, there are no bibliometric studies exploring NSCLC IO-based trials. We aimed to provide a systematic and comprehensive analysis of the design, reporting, population, and disparities of phase 3 trials investigating IO for advanced NSCLC. Methods: MEDLINE search was performed (last decade) for phase 3 trials reporting on patients with advanced (stage IIIA or higher) NSCLC. We assessed relationships between study outcomes, funding transparency, conflict of interest, journal impact factor (IF), region, gender of the first and last authors, population size, and ethnicity. Results: From 2012 to 2022, 2556 articles were screened and 81 were included. Overall survival (OS), followed by progression/disease-free survival (PFS) and overall/objective response (ORR) were the most commonly reported primary endpoints, representing 54%, 44%, and 15% respectively. The majority of the studies ( &gt; 97%) had a funding sources statement and declared COI. Male first and last authorship represented 84% and 74% of studies, respectively. In 62% of trials reporting the patient’s ethnicity, white was the most common (65%). Regarding the source of funding, 74% of trials reported industry-only, 8% academia-only, 11% combined, 4% no funding received and 2.5% were not transparent. 98% of trials were from high-income countries (HIC), being the US (37%) and China (26%) the most reported. The mean number of authors with declared COI was 10.55 [0-25] and the mean total number of authors was 21.3 [5-76]. Publications journals' mean IF was 57.7 [2.1-202.7]. COI declaration was associated with publication in a journal with a higher IF compared to studies with no declared COI (p &lt; 0.05). The journal IF was significantly higher in the US publications compared to China (p &lt; 0.01). Trials assessing OS and PFS as their primary outcome were published with a higher IF in relation to assessing ORR only (p &lt; 0.05). There was a significant association between the first and last authors' gender (p &lt; 0.05), with a higher likelihood of matching genders (OR = 4,5 [1,3-14,4]). There was no association between the proportion of COI among authors, source of funding, and first author’s gender with journal IF. Conclusions: Phase 3 trials exploring IO for advanced NSCLC are majorly done in HIC, report industry funding and COI, and have males as the first and last authors. PFS is the primary outcome of almost 50% of the trials. We identified that among the primary outcomes studied, declaration of COI and author’s geographic affiliation may influence the publication’s IF. Sustained efforts are required to guarantee impartial reporting of clinical trial results and inclusive representation.
An analysis of breast cancer index scores predicting benefit of extended endocrine therapy by race.
Authors: Nicholas Siu-Li, Ian Pagano, Jami Aya Fukui
Journal: Journal of Clinical Oncology (2023)

549 Background: Patients with early-stage hormone receptor-positive (HR+) breast cancer have a good prognosis. Prior studies have shown that extending endocrine therapy beyond the first 5 years reduces the risk of late distant recurrence. The Breast Cancer Index (BCI) is a gene expression assay that provides both a prognostic risk of late distant recurrence in addition to a yes/no prediction of benefit from receiving extended endocrine therapy. To date, no studies have examined the relationship between race and BCI score. This study aims to investigate the interaction between race and BCI scores in women with early-stage HR+ breast cancer. Methods: We analyzed BCI scores, demographics, and tumor characteristics from 89 women diagnosed with early-stage HR+ breast cancer. Univariate logistic regression analysis was run using race, BCI recurrence risk, hormone status, tumor size, or tumor grade as predictor variables. BCI prediction of benefit was used as the outcome variable. Results: Compared to Caucasians, Native Hawaiians had significantly greater odds of having a BCI score predicting benefit from receiving extended endocrine therapy (OR = 7.00, p = 0.04). Additionally, there were significantly greater odds of having a score predicting benefit among those who had a recurrence risk of 5-10% (OR = 3.84, p = 0.04), or ≥10% (OR = 9.16, p &lt; 0.001) compared to a recurrence risk &lt; 5%. Conclusions: Our findings highlight the utility of characterizing differences in BCI predictive and prognostic scores by race among breast cancer patients with early-stage HR+ tumors. Notably, Native Hawaiian women had 7.0 times increased odds of having a score predicting benefit of extended endocrine therapy compared to Caucasians. This result is salient given the high incidence of breast cancer among Native Hawaiians. Though not statistically significant, our data also demonstrated Filipinos had increased odds of a score predicting benefit as well. Furthermore, our findings show a direct correlation between prognostic risk of late distant recurrence and predictive benefit of extended endocrine therapy with a higher odds ratio associated with higher recurrence risk. Our study shows notable differences in BCI findings when stratifying patients by race. However, our sample size is relatively small, and we lack sufficient data from patients representing other races such as Hispanic and Black. Future studies may expand the sample size and adjust for known breast cancer risk factors. The goal is to identify trends that may improve our usage of the BCI as a tool to effectively guide hormone therapy recommendations in patients with early-stage HR+ breast cancer. [Table: see text]
Clinical practice guideline descriptions of oncologic drugs granted FDA accelerated approval: A cross-sectional study.
Authors: Maryam Mooghali, Joshua David Wallach, Aaron Philip Mitchell, Joshua J Skydel, Joseph S. Ross, Reshma Ramachandran
Journal: Journal of Clinical Oncology (2023)

1590 Background: The Food and Drug Administration’s (FDA's) accelerated approval (AA) pathway allows drugs to be approved using surrogate endpoints, while requiring that sponsors complete postmarketing requirement (PMR) studies verifying clinical benefit. Subsequently, FDA determines whether AA can be converted to standard approval or be withdrawn. It is unclear whether clinical practice guidelines reflect PMR results or FDA regulatory decisions. As most drugs granted AA are cancer therapies, we investigated whether and how National Comprehensive Cancer Network (NCCN) guidelines reflect underlying evidence supporting AAs and subsequent FDA decisions. Methods: In this cross-sectional study, we used Drugs@FDA to identify drug indications granted AA by FDA for oncologic indications from 2016-2018, PMR status and results, and whether AA was converted to regular approval or withdrawn. We excluded pediatric and tumor-agnostic indications. PMR studies were classified as positive if the results from primary efficacy endpoint were statistically significant ( P&lt;0.05) favoring the drug. For each AA indication, we searched relevant NCCN guidelines for their recommendations and examined if AA status, PMR results, and updated FDA decisions were reflected. Results: Among 36 oncology drug indications granted AA from 2016 to 2018, 29 (81%) NCCN guidelines did not mention that the drug was approved via AA pathway or had not yet verified clinical benefit. For all 36 (100%) indications, NCCN guidelines did not state that approval was based on surrogate endpoints. As of December 31, 2022, among 16 drug indications that were converted to standard approval, 13 (81%) guidelines reflected FDA’s updated decisions. Among 8 indications withdrawn after AA, 5 (63%) guidelines reflected the withdrawn status. Of 6 drug indications with negative PMR study results that were withdrawn, 2 (33%) were still recommended in NCCN guidelines thereafter. Conclusions: NCCN guidelines do not consistently reflect FDA regulatory status or PMR study results, highlighting the need for more up-to-date and accurate information to guide clinical practice.[Table: see text]
Distribution and outcomes of HER2-low and HER2-zero metastatic breast cancer in Black and younger women.
Authors: Paola Zagami, Yara Abdou, Alexis Caroline Wardell, Allison Mary Deal, Amy Wheless, Elizabeth Claire Dees, Lisa A. Carey
Journal: Journal of Clinical Oncology (2023)

1109 Background: Black and younger patients with breast cancer (BC) have higher mortality. This racial disparity has been attributed to different BC biology, access to care, and treatment. With the advent of new antibody-drug conjugates (ADC) for metastatic BC (MBC), “HER2-negative” has been subdivided into HER2-low (IHC 1+ or 2+/ISH-negative) and HER2-0 (IHC 0). Little is known about these subcategories among Black and younger women with MBC. Methods: Clinical characteristics, treatment, and outcomes of patients diagnosed with HER2-negative MBC between 2011-2022 and with follow-up through a progression-free survival event on first-line therapy (PFS1) were retrieved from the UNC Metastatic Breast Cancer Database; hormone receptor (HR) and HER2 categories were by clinical criteria from the pathology report. Analyses were limited to HER2-negative BC and stratified/controlled by HR status. Fisher’s exact tests were used to compare HER2 status across race and age. The Kaplan Meier method and log-rank tests, as well as Cox proportional hazards models estimated PFS1. Results: The cohort included 772 MBC patients (56% HER2-low and 44% HER2-0), 22% Black women and 30% &lt; 50 years old at MBC diagnosis. There were no differences in proportion with HER2-low by race or age (p&gt;0.5). Patients with HER2-low had better observed median PFS1 compared to HER2-0, however, most of these differences were non-significant: overall (HR+ 12.2 vs 9.8m, p=0.11, HR- 4.3 v 3.3m, p=0.29) and within race and age categories (see table). In Cox modeling, Black women had worse PFS1 (p=0.03), that was no longer apparent after adjusting for HR status (p=0.1), there was no difference by age. Patients with HER2-0 had worse PFS1 (p=0.0005), which remained after adjusting for HR status (p=0.05). In a multivariable model comparing HER2-0 to HER2-low, adjusting for race and HR status, PFS1 remained shorter in the HER2-0 group (hazard ratio: 0.84, CI 0.692 – 1.015, p=0.07). Among those treated with uniform first-line therapy, better PFS1 was observed in HER2-low disease. This included 137 HR+ MBC treated with ET + CDK4/6i (mPFS1 14.3 v 10.3m, p=0.33) and 170 HR- MBC treated with chemotherapy (mPFS1 4.0 v 3.1m, p=0.22) with no variation by race or age. Conclusions: Within HER2-negative MBC, distribution of HER2-low and HER2-0 cancers does not differ by race and age. The clinical benefit of first-line therapy is strongly driven by HR status regardless of race and age, and is greater in HER2-low cancers although this cohort did not include HER2-directed ADCs. [Table: see text]
Does RSClin provide additional information over classic clinico-pathologic scores (PREDICT 2.1, Influence, CTS-5)? A TEAM Pathology substudy.
Authors: Ana-Alicia Beltran-Bless, Gregory Russell Pond, Jane Bayani, Sarah Barker, Melanie Spears, Elizabeth Mallon, Karen J Taylor, Annette Hasenburg, Christos Markopoulos, Luc Yves Dirix, Caroline M. Seynaeve, Cornelis J.H. Van De Velde, Daniel William Rea, Lisa Vandermeer, John Frederick Hilton, John Bartlett, Mark J. Clemons
Journal: Journal of Clinical Oncology (2023)

533 Background: Gene-expression profiling tests (e.g. Oncotype, Mammaprint, Prosignia, Breast Cancer Index and EndoPredict) are widely used in the care of patients with early-stage hormone positive breast cancer (node negative or 1-3 lymph nodes). However, these tests are resource intensive, and few studies have compared their value with either free and widely available clinico-pathologic risk calculators (e.g. PREDICT 2.1, INFLUENCE 2.0, and CTS-5) or tools that combine genomic testing with clinico-pathologic data (e.g. RSClin). The TEAM pathology substudy population was used to compare these different predicted model scores with outcomes. Methods: The TEAM pathology study consists of 3284 postmenopausal hormone positive breast cancer patients treated with either exemestane or tamoxifen followed by exemestane. Accrual was from 2001 to 2006. Genes comprising the multi-parametric Oncotype Dx were used to train signatures to create true assay results. Patient data was then used to calculate recurrence scores through various tools. This included clinico-pathologic models and their respective endpoints PREDICT 2.1 (overall survival at 5 years), INFLUENCE 2.0 (distant metastasis at 5 years), CTS-5 (distant recurrence risk at year 5-10), the purely genomic Oncotype Dx trained results (distant recurrence risk at 9 years), as well as the new clinico-pathologic RSClin (distant recurrence risk at 10 years). We compared the level of association between these predictive model scores using Spearman correlation coefficients. The prognostic ability of each model was contrasted for each outcome using Harrell’s C-statistic. Results: Results were available for CTS-5 (3022 patients), INFLUENCE 2.0 (3485 patients), ODx-trained (3825 patients), and RSClin (3029 patients). Correlation coefficients showed low correlation between Influence ( r= 0.25) and CTS-5 ( r= 0.17) with Oncotype-Dx trained results, and high correlation between RSClin ( r = 0.84) and Oncotype-Dx trained results. The concordance index was similar (0.65 to 0.68) for all models with distant metastasis-free survival as the outcome. Analysis is ongoing and further results will be available at the time of presentation. Conclusions: Other clinico-pathologic tools such as Influence 2.0 and CTS-5 have good prognostic ability when compared to Oncotype Dx-trained results and RSClin. [Table: see text]
Incidence of hypomagnesemia in patients with HER2+ breast cancer treated with pertuzumab.
Authors: Nirja Shah, Karen Colleen Daily
Journal: Journal of Clinical Oncology (2023)

e12569 Background: Breast cancer is the most common cancer diagnosed in women. HER2 gene amplification/protein overexpression is seen in about 20% of breast cancer cases. Pertuzumab (P), an EGFR inhibitor, is a monoclonal antibody administered with Trastuzumab in the treatment of HER2-positive breast cancer. Breast oncologists across multiple institutions have noted hypomagnesemia in patients receiving P-containing regimens. Retrospective data from Memorial Sloan Kettering Cancer Center and University of Florida Health have reported the incidence of hypomagnesemia in patients treated with P neoadjuvantly (8/90 and 7/25, respectively). Cetuximab and Panitumumab, also EGFR inhibitors, are well known to cause hypomagnesemia. Hypomagnesemia can be clinically associated with convulsions, atrial tachycardias, hypocalcemia and hypokalemia. This prospective study details the incidence, severity, and timeline of hypomagnesemia in HER2-positive breast cancer patients treated with P. Methods: 27 eligible patients were identified at two institutions through medical oncology clinic visits and weekly tumor board screenings. Inclusion criteria was HER2+ breast cancer patients initiating treatment with P. Patients receiving platinum agents were excluded (8/27). Following informed consent, magnesium levels were obtained along with standard of care comprehensive metabolic panels at the first four P infusions (19/27). Results: A one-sample binomial test was used to compare the proportion of hypomagnesemia at 3 months among subjects who receive P with 2% (historical control). Results demonstrated that only one patient developed a magnesium level below normal range, resulting in no significant difference with historical control (P = 0.291) This patient’s magnesium level was low at baseline and did not significantly improve or worsen throughout treatment with P. Conclusions: There was no significant incidence of hypomagnesemia noted in HER2+ breast cancer patients treated with P. This emphasizes the safety of P in patient populations prone to developing hypomagnesemia such as those receiving concurrent Carboplatin. Our results do not indicate clinical monitoring of hypomagnesemia is necessary for patients receiving P. [Table: see text]
VERITAC-2: A global, randomized phase 3 study of ARV-471, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, vs fulvestrant in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer.
Authors: Mario Campone, Cynthia X. Ma, Michelino De Laurentiis, Hiroji Iwata, Sara A. Hurvitz, Seth Andrew Wander, Michael A. Danso, Dongrui Ray Lu, Julia Perkins Smith, Yuan Liu, Lana Tran, Sibyl Anderson, Erika P. Hamilton
Journal: Journal of Clinical Oncology (2023)

TPS1122 Background: ARV-471 is an oral PROTAC ER degrader that binds to and degrades wild-type ER and clinically relevant mutants. ARV-471 directly recruits the ubiquitin-proteasome system to degrade ER, whereas selective ER degraders (SERDs) indirectly cause ER degradation. In a first-in-human phase 1/2 study, ARV-471 monotherapy was well tolerated and showed clinical activity in heavily pretreated patients with ER+/HER2- advanced breast cancer. The phase 3 monotherapy dose (200 mg once daily [QD]) was chosen due to comparable efficacy and favorable tolerability relative to 500 mg QD and robust ER degradation in paired tumor biopsies. The randomized phase 3 VERITAC-2 study (NCT05654623) will compare efficacy and safety of ARV-471 vs the SERD fulvestrant in patients with ER+/HER2- advanced breast cancer after prior combination cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy and endocrine therapy (ET). Methods: Eligible patients (aged ≥18 years) have a confirmed diagnosis of ER+/HER2- locoregional recurrent or metastatic breast cancer not amenable to surgical resection or radiation; 1 prior line of combination CDK4/6 inhibitor therapy and ET; ≤1 additional line of ET; most recent ET given for ≥6 months before disease progression; and radiological disease progression during or after the last line of therapy. Prior chemotherapy in the locally advanced or metastatic setting and prior fulvestrant are not permitted. Patients (N~560) are randomized 1:1 to receive 200 mg ARV-471 orally QD continuously or fulvestrant intramuscularly on days 1 and 15 in the first 28-day cycle and on day 1 in subsequent cycles; patients are stratified by ESR1 mutation status and presence of visceral disease. The primary endpoint, progression-free survival, will be assessed by blinded independent central review in the intention-to-treat population and the ESR1 mutation sub-population. Secondary outcome measures include overall survival, antitumor activity (objective response rate, duration of response, and clinical benefit rate), safety, and quality of life assessments. Clinical trial information: NCT05654623 .
Integrating radiation therapy with CDK4/6 inhibitors for breast cancer: A systematic review and meta-analysis of toxicity.
Authors: Carlotta Becherini, Luca Visani, Anna Kirby, Indrani S. Bhattacharya, Gilberto Morgan, Viola Salvestrini, Charlotte E Coles, Javier Cortés, Evandro de Azambuja, Nadia Harbeck, Clare Isacke, Orit Kaidar-Person, Elisabetta Marangoni, Birgitte Vrou Offersen, Hope S. Rugo, Andrea Morandi, Matteo Lambertini, Philip Poortmans, Lorenzo Livi, Icro Meattini
Journal: Journal of Clinical Oncology (2023)

e13075 Background: Over the past years, the treatment landscape of breast cancer (BC) has significantly evolved. Several new anticancer agents entered clinical use. Among them CDK4/6i have revolutionised both curative and advanced BC scenarios. The availability of new drugs raises the crucial question on how to integrate them with local and regional treatments. Strong levels of evidence on the safety profile of CDK4/6i in combination with different RT techniques or schedules are currently missing. We aim to systematically review and summarise the published data on the safety profile of palliative and ablative RT combined with CDK4/6i in early and metastatic BC settings. Methods: A literature search (PUBMED/MedLine, Embase, and Cochrane databases) was conducted to identify original studies on the safety profile of the combination of CDK4/6i with RT. This systematic review and meta-analysis project is part of the ESTRO Guidelines Committee consensus recommendations on integration of RT with targeted treatments for breast cancer, an initiative developed by a multidisciplinary Core Group and Expert Panel of medical, clinical, radiation oncologists, preclinical specialists, and patient advocates. Results: Eleven articles finally met all eligible criteria and were included in the meta-analysis. Data could not be collected in the adjuvant setting due to lack of data in the current literature. Pooling data of the included studies show a moderate incidence of hematological toxicities grade 3+ (21.0 %) and a very low-grade 3+ non-hematological toxicity were observed. Conclusions: The safety profile of CK4/6i and RT combination is acceptable. However, international consensus guidelines regarding the safety issue of CDK4/6i and RT combination for breast cancer are warranted.
Influence of ovarian function supression on quality of life in breast cancer survivors during adjuvant endocrine therapy.
Authors: Natalija Dedic Plavetic, Ana Dugonjic Okrosa, Tajana Silovski, Josipa Jovic Zlatovic, Lana Jajac Brucic, Marko Skelin, Iva Mucalo
Journal: Journal of Clinical Oncology (2023)

560 Background: Adding ovarian function suppression to adjuvant endocrine therapy (AET) lowers the disease recurrence rates among premenopausal women with hormone receptor-positive (HR+) early breast cancer (EBC). However, a detrimental effect on endocrine symptoms burden (ESB) is expected. Therefore, this study aimed to investigate differences in Quality of life (QoL) and endocrine symptoms in premenopausal women prescribed AET, with/without gonadotropin-releasing hormone agonist (GnRH). Methods: This cross-sectional study included women, with HR+ EBC, premenopausal at diagnosis, treated with AET for more than 3 months, with and without GnRH. The research was conducted with institutional Ethics Committee approval at the University Hospital Centre Zagreb, General Hospital Šibenik, and with online survey. A validated instrument, the Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES), was used. The collected data were analysed using SPSS v. 29 (p≤0.05). Results: Overall, 314 eligible BC survivors with a median age of 45 years (22-65) and a median duration of AET of 2 years (3 months -12 years) responded to FACT-ES and were included in the analysis. Altogether 45.2% (n=142) of participants were prescribed tamoxifen (TAM), 25.8% (n=81) GnRH+TAM, and 29% (n=91) GnRH+aromatase inhibitor (AI); exemestane (9%), letrozole (13.6%) and anastrozole (6.4%). The total QoL (FACT-ES) score was higher in patients treated with TAM as opposed to patients treated with AI+GnRH (p=0.01). Adding GnRH to TAM did not significantly change QoL when compared to TAM alone or AI+GnRH. In addition, patients on AI+GnRH had lower physical well-being (PWB) score than patients on TAM+GnRH (p=0.03) or TAM alone (p=0.05) and lower endocrine subscale score (ESS-19) than patients on TAM (p=0.01), indicating more endocrine symptoms in premenopausal women treated with AI+GnRH. Among patients treated with AI+GnRH letrozole had lower PWB (p=0.03) and ESS-19 score (p=0.01) than exemestane. Conclusions: This study showed that GnRH+AI in premenopausal women with HR+ EBC results in greater ESB and lower QoL compared to patients treated with TAM or GnRH+TAM. Therefore, interventions helping decrease the ESB in patients treated with AI+GnRH should be explored and developed to help patients adhere to and persist in AET. [Table: see text]